Synthesis and Secretion of Insulin-Like Growth Factor and Its Binding Protein by the Perfused Rat Liver: Dependence on Growth Hormone Status*

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Abstract
Isolated livers of normal and hypophysectomized (hypox) rats with or without GH [growth hormone] replacement therapy were perfused in an erythrocyte-free recirculating perfusion system for 4 h in the presence of [35S]cysteine. Albumin secretion and synthesis increased in a parallel and linear fashion over 4 h. The albumin secretion rates were 0.53 and 0.21 mg/g liver h-1 in normal and hypox animals, respectively. Insulin-like growth factor (IGF) secretion, measured as insulin equivalents in the fat cell assay as well as in a competitive protein binding assay, and IGF synthesis, as determined from [35S]cysteine incorporation into immunoprecipitable IGF, likewise increased linearly and in parallel throughout the perfusion time. The IGF secretion rate was 50 .mu.U/g liver h-1. The secreted IGF had a MW of .apprx. 7700 daltons. Secretion and synthesis of IGF were reduced to 11% in hypox rats and were largely restored by human GH replacement therapy (to 86% of normal). A single specific binding protein with an approximate MW of 35,000 was detected in the perfusate. The binding protein was measured by covalent cross-linkage to [125I]IGF I by dimethylsuberimidate. The secretion of this binding protein was 62% of normal in hypox animals and 79% in GH-treated hypox rats. Apparently IGF is continuously synthesized and released by the liver. Assuming a half-life for IGF of 3 h in the normal rat, a plasma volume of 8 ml, and a liver wt of 8.5 g, the rate of IGF production by the perfused normal rat liver (50 .mu.U/g liver h-1) would be sufficient to maintain serum IGF at the concentration determined in normal rat serum (.apprx. 130 .mu.U/ml). Apparently the liver is the major site of IGF production in the rat.